Rational Design and Greener Synthesis of Selenylated Indolamides as Potential Anti-Alzheimer’s Agents

This study presents the rational design and sustainable synthesis of selenylated indolamides as potential therapeutic agents for Alzheimer's disease. Through computational approaches, including molecular docking and pharmacokinetic analyses, we identified key structural modifications that improve acetylcholinesterase inhibition, a critical target for AD treatment. We employed an environmentally benign I₂/DMSO oxidation system to optimize the synthetic protocol, enabling the efficient selenylation of 27 indolamide derivatives (<b>5a-6a</b>) via a straightforward and practical transformation, delivering high yields of up to 99%. Importantly, the methodology proved scalable, delivering an 88% yield on a gram-scale reaction. <i>In silico</i> ADMET predictions using the pkCSM platform indicated that C2-selenylated indolamides possess an improved safety profile and promising pharmacokinetic properties, suggesting their potential for further drug development. In particular, compounds <b>5a</b> and <b>5y</b> demonstrated the best balance between reaction yield and docking score (94% and 86.17; 98% and 93.71, respectively). These findings highlight the significance of incorporating green chemistry principles alongside advanced in silico methodologies to drive innovation in drug discovery.